The present invention relates generally to the field of biocompatible prosthetic devices having increased resistance to mineralization and thrombus formation. More particularly, it concerns biocompatible heart valves comprising an effective amount of a thrombus-inhibiting and mineralization-inhibiting coating. The present invention also features a novel method for manufacturing heart valves comprising an effective amount of a thrombus-inhibiting and mineralization-inhibiting coating.
Continuing advances in heart valve prosthesis design and techniques for implantation have improved the survival length and quality of life of patients who receive these devices. In an ongoing effort to develop a more durable and compatible heart valve prosthesis, researchers have used a variety of techniques to determine the suitability of given valve materials for a given implant application. This suitability is generally known as xe2x80x9cbiocompatibility.xe2x80x9d Researchers commonly deal with biocompatibility in terms of whether the implant material or its degradation products, if any, initiate adverse tissue responses in the host, or conversely, whether deleterious changes in the chemical, physical, or mechanical properties of the implant material are caused by the host environment. The term xe2x80x9chemocompatibilityxe2x80x9d refers to biocompatibility issues related with implantation in the cardiovascular system, such as any toxicity of implant materials to red blood cells or tissues contacted by the material. The vast majority of biocompatibility studies to date have involved animal models. The ultimate test for biocompatibility of a material, device, or prosthesis is human implantation.
To be clinically effective, a heart valve must endure a difficult environment, including cyclic bending stresses and high pressure spikes across the valve, for long periods of time. Prosthetic heart valves currently in clinical use are of two general varieties: mechanical or tissue. Mechanical heart valves are very durable, but their use is complicated by higher risks of thromboembolism, hemorrhage, and hemolysis. Tissue valves require no chronic anticoagulation of the patient, but often fail due to mineralization (the formation of mineral deposits, e.g. calcium phosphates) and tissue tearing. Potential alternative materials that are sufficiently durable and blood compatible for use in a prosthetic heart valve include (i) non-glutaraldehyde fixed bovine pericardial tissue, which studies in an ovine mitral model show to be mineralized to a lesser extent than glutaraldehyde-fixed tissue and (ii) synthetic polymers, such as polyurethanes, which have been reported in many different models to also show less mineralization than glutaraldehyde-fixed bovine pericardial tissue.
Mineralization, however, remains an obstacle to the clinical development of a polymer-based heart valve. Artificial heart valve bladders and pacemaker leads fabricated of polyurethane have been observed to undergo mineralization in mammalian trials. The precise mechanism for pathological mineralization of cardiovascular tissue or heart valve prostheses is not well understood. Generally, the term xe2x80x9cpathologic mineralizationxe2x80x9d refers to deposition of minerals, typically calcium phosphate mineral salts, in association with a disease process. See Schoen et al., xe2x80x9cBiomaterial-assisted calcification: Pathology, mechanisms, and strategies for prevention,xe2x80x9d J. Biomed. Mater. Res.: Applied Biomaterials, Vol. 22 A1, 11xe2x80x9436 (1988), incorporated herein by reference. Mineralization may be due to host factors, implant factors, or extraneous factors such as mechanical stress. Some evidence suggests calcium deposits are related to devitalized cells, especially membrane cells, where the calcium pump (Ca+2-Mg+2-ATPase) responsible for maintaining low intracellular calcium levels is weakened or no longer functioning. Mineralization has been observed to begin with an accumulation of calcium and phosphorous (present as hydroxyapatite and other calcium phosphates), which develops into nodules that can eventually lead to a valve failure.
A permanent implantable prosthetic polymeric heart valve was first described at least four decades ago (Akutsu, T., Dreyer, B., Kolff, W. J., J. Appl. Physiol. 14:1045-1048 (1959)), yet reduction of the concept to clinical practice has eluded the medical device industry, due to leaflet stiffening, tearing, thrombosis, calcification, and valve stenosis not predicted by in vitro models. Reported physical properties of materials such as polyetherurethanes exceed the requirements of cardiac valves. Biomer, a polyetherurethane urea once thought to be the ideal blood contacting material for implantable devices such as heart valves, was later reported to be prone to mineralization in the juvenile sheep model (Hilbert, S. L. et al., J. Thorac. Cardiovasc. Surg. 94: 419-429 (1987)), and its use as a primary component of a clinical prosthetic heart valve has not materialized. While the observed mineralization was first attributed to microscopic defects in the leaflet surface, it was later appreciated that the polyether segment of the polyurethane had the capacity to associate with calcium ions in the blood leading to mineralization of the material itself (Thoma, R. J. et al., J. Biomat. Appl. 3:180-206 (1988)). Reports of mineralized polyurethane blood pump bladders supported the polyurethane mineralization theory (Coleman, D. L. Trans. Am. Soc. Artif. Intern. Organs 27: 708-713 (1981)). However, it was not appreciated that mineralized thrombus comprised the vast majority of the calcium present upon polymer valve leaflets, and therefore, for materials not inherently calcific, inhibition of leaflet thrombosis simultaneously prevents leaflet calcification.
The location of mineralization sites on a heart valve prosthesis may be intrinsic, i.e., within the boundaries of the biomaterials of the prosthesis, or extrinsic, i.e., outside the biomaterials, though possibly attached to the valve prosthesis, e.g., within thrombus or other adherent tissue. With polymer valves, it is generally believed that both intrinsic and extrinsic mineralization must be controlled. Therefore, a biocompatible heart valve prosthesis is needed that is resistant not only to thrombus formation, but also to mineralization, particularly extrinsic mineralization, i.e., mineralization of thrombus or tissue adherent to valve leaflets.
This invention relates to biocompatible prostheses that are resistant to in vivo mineralization. More particularly, this invention relates to mineralization-resistant and thrombus-resistant heart valves comprising synthetic polymers or materials of natural origin (e.g. bovine pericardium, porcine heart valves, or homografts), having incorporated therein an effective amount of a coating to impart resistance to both mineralization and thrombus formation.
This invention is also directed to a prosthetic heart valve comprising a stent defining a blood flow path and a plurality of leaflets, each leaflet having incorporated therein an effective amount of an applied coating to render the heart valve resistant to in vivo pathologic thrombus formation and resistant to in vivo pathologic mineralization. The heart valve can comprise synthetic polymers or materials of natural origin. Preferably, the leaflets comprise silicone rubber or phosphonate modified polyetherurethane.
The coating may be applied photochemically or by other coating techniques known in the art (e.g., wet chemistry), and is preferably derived from a precursor of the formula:
Xxe2x80x94Yxe2x80x94Z
wherein X is a chemically reactive group capable, upon activation, of bonding to the surface of the heart valve; Y is either null or a relatively inert skeletal moiety resistant to cleavage in aqueous physiological fluids; and Z is a functionally active moiety or a biocompatible agent. In a preferred embodiment, X is a photochemically reactive group.
This invention further provides a method for reducing mineralization and thrombus formation in a bioprosthetic heart valve after implantation in an animal. The method comprises:
contacting, prior to implantation, at least a portion of the heart valve with a coating precursor of the formula:
Xxe2x80x94Yxe2x80x94Z
wherein X is a chemically reactive group capable, upon activation, of bonding to the surface of the heart valve; Y is either null or a relatively inert skeletal moiety resistant to cleavage in aqueous physiological fluids; and Z is a functionally active moiety or a biocompatible agent; and
bonding the precursor to at least a portion of the heart valve, to produce a heart valve with a bonded coating,
wherein the bonded coating is present in an amount effective to reduce mineralization and thrombus formation after implantation. In a preferred embodiment, X is a photochemically reactive group, and the precursor is bonded to at least the leaflets of the heart valve.